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https://www.readbyqxmd.com/read/28653352/individualised-dosing-algorithms-and-therapeutic-monitoring-for-antiepileptic-drugs
#1
Sven C van Dijkman, Sebastian G Wicha, Meindert Danhof, Oscar E Della Pasqua
Pharmacokinetic (PK) models exist for most antiepileptic drugs (AEDs). Yet, their use in clinical practice to assess inter-individual differences and derive individualised doses has been limited. Here we show how model-based dosing algorithms can be used to ensure attainment of target exposure and improve treatment response in patients. Using simulations, different treatment scenarios were explored for 11 commonly used AEDs. For each drug, five scenarios were considered: i. all patients receive the same dose...
June 27, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28647832/genetic-dissection-of-adventitious-shoot-regeneration-in-roses-by-employing-genome-wide-association-studies
#2
Thi Hong Nhung Nguyen, Dietmar Schulz, Traud Winkelmann, Thomas Debener
We analysed the capacity to regenerate adventitious shoots in 96 rose genotypes and found 88 SNP markers associated with QTLs, some of which are derived from candidate genes for shoot regeneration. In an association panel of 96 rose genotypes previously analysed for petal colour, we conducted a genome-wide association study on the capacity of leaf petioles for direct shoot regeneration. Shoot regeneration rate and shoot ratio (number of shoots/total number of explants) were used as phenotypic descriptors for regeneration capacity...
June 24, 2017: Plant Cell Reports
https://www.readbyqxmd.com/read/28643852/therapeutic-d2-3-receptor-occupancies-and-response-with-low-amisulpride-blood-concentrations-in-very-late-onset-schizophrenia-like-psychosis-vloslp
#3
Suzanne Reeves, Kate Eggleston, Elizabeth Cort, Emma McLachlan, Stuart Brownings, Akshay Nair, Suki Greaves, Alan Smith, Joel Dunn, Paul Marsden, Robert Kessler, David Taylor, Julie Bertrand, Robert Howard
OBJECTIVE: Antipsychotic drug sensitivity in very late-onset schizophrenia-like psychosis (VLOSLP) is well documented, but poorly understood. This study aimed to investigate blood drug concentration, D2/3 receptor occupancy and outcome in VLOSLP during open amisulpride prescribing, and compare this with Alzheimer's disease (AD). METHODS: Blood drug concentration, prolactin, symptoms and extrapyramidal side-effects (EPS) were serially assessed during dose titration...
June 23, 2017: International Journal of Geriatric Psychiatry
https://www.readbyqxmd.com/read/28643374/population-pharmacokinetic-and-pharmacodynamic-modeling-of-ly2510924-in-patients-with-advanced-cancer
#4
S Bihorel, E Raddad, J Fiedler-Kelly, J R Stille, J Hing, E Ludwig
The objectives of this study were to characterize the pharmacokinetics (PK) of LY2510924, a potent peptide antagonist of the CXCR4 receptor, after subcutaneous administration in patients with advanced cancer forms and quantify LY2510924 stimulatory effects on the mobilization of cells bearing the cluster of differentiation 34 (CD34) as an indirect reflection of the chemokine C-X-C motif ligand 12/CXCR4 axis inhibition. LY2510924 PK were best characterized by a 2-compartment model with first-order absorption and dose-dependent clearance predicting steady state after three daily doses and little accumulation (accumulation ratio <1...
June 23, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28642710/tacrolimus-updated-guidelines-through-poppk-modeling-how-to-benefit-more-from-cyp3a-pre-emptive-genotyping-prior-to-kidney-transplantation
#5
Jean-Baptiste Woillard, Michel Mourad, Michael Neely, Arnaud Capron, Ron H van Schaik, Teun van Gelder, Nuria Lloberas, Dennis A Hesselink, Pierre Marquet, Vincent Haufroid, Laure Elens
Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD]) profile. Part of this variability is explained by genetic polymorphisms affecting the metabolic pathway. The integration of CYP3A4 and CY3A5 genotype in tacrolimus population-based PK (PopPK) modeling approaches has been proven to accurately predict the dose requirement to reach the therapeutic window...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28636998/physiologically-based-pharmacokinetic-modeling-for-predicting-irinotecan-exposure-in-human-body
#6
Yingfang Fan, Najia Mansoor, Tasneem Ahmad, Rafeeq Alam Khan, Martin Czejka, Syed Sharib, Dong-Hua Yang, Mansoor Ahmed
Colorectal cancer is the third leading cause of cancer-related deaths in the United States. Treatment of colorectal cancer remains a challenge to clinicians as well as drug developers. Irinotecan, a Camptothecin derivative, is successfully used for the treatment of this rapidly progressing malignancy and finds its place in the first line of therapeutic agents. Irinotecan is also effective in treating SCLC, malignant glioma and pancreatic adenocarcinoma. However, its adverse effects limit its clinical application...
June 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636311/insights-into-integrated-lead-generation-and-target-identification-in-malaria-and-tuberculosis-drug-discovery
#7
John Okombo, Kelly Chibale
New, safe and effective drugs are urgently needed to treat and control malaria and tuberculosis, which affect millions of people annually. However, financial return on investment in the poor settings where these diseases are mostly prevalent is very minimal to support market-driven drug discovery and development. Moreover, the imminent loss of therapeutic lifespan of existing therapies due to evolution and spread of drug resistance further compounds the urgency to identify novel effective drugs. However, the advent of new public-private partnerships focused on tropical diseases and the recent release of large data sets by pharmaceutical companies on antimalarial and antituberculosis compounds derived from phenotypic whole cell high throughput screening have spurred renewed interest and opened new frontiers in malaria and tuberculosis drug discovery...
June 21, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28636184/pharmacokinetics-pharmacodynamics-of-bococizumab-a-monoclonal-antibody-to-pcsk9-after-single-subcutaneous-injection-at-3-sites-nct-02043301
#8
Ellen Q Wang, Anna Plotka, Joanne Salageanu, Catherine Sattler, Carla Yunis
AIM: To characterize the single-dose pharmacokinetics (PK) and pharmacodynamics (PD) of bococizumab, a monoclonal antibody inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), administered subcutaneously (s.c.) to the abdomen, thigh, or upper arm (NCT02043301). METHODS: Seventy-five adults with low-density lipoprotein cholesterol (LDL-C) ≥130 mg/dL and not on background lipid-lowering therapy were randomized (1:1:1) to a single 150-mg s.c. dose of bococizumab administered to the abdomen, thigh, or upper arm...
June 21, 2017: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/28634121/population-pharmacokinetics-of-tobramycin-inhalation-solution-in-pediatric-patients-with-cystic-fibrosis
#9
Xinting Wang, Stephan Koehne-Voss, SivaNaga S Anumolu, Jing Yu
Tobramycin inhalation solution (TOBI) given as a twice-daily inhalation of nebulized aerosols of 300 mg is approved for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients over 6 years of age. To investigate tobramycin pharmacokinetics (PK) after inhalation of TOBI in pediatric CF patients below 7 years, a population PK approach was used to evaluate tobramycin PK data in patients 6 months to 44 years of age from four clinical studies. The final model used a two-compartmental, first-order absorption model with effect of body mass index on the apparent central volume of distribution...
June 17, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28631514/pharmacokinetics-and-dosing-requirements-of-digoxin-in-pregnant-women-treated-for-fetal-supraventricular-tachycardia
#10
Ana Martin-Suarez, Jose German Sanchez-Hernandez, Fabiola Medina-Barajas, Jonas Samuel Perez Blanco, Jose M Lanao, Luisa Garcia-Cuenllas Alvarez, M Victoria Calvo
BACKGROUND: The objective of this study was to characterize the pharmacokinetics (PK) of digoxin in pregnant women and its potential implications for drug dosing. METHODS: Serum digoxin concentrations (SDCs) obtained in pregnant women treated for fetal supraventricular tachycardia (SVT) was retrospectively collected. PK analysis was comparatively performed using a two-stage approach (PKS™) and a Population PK approach (NONMEM™). As clinical outcome the fetal heart rate was recorded...
June 20, 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28624123/population-pharmacokinetic-pharmacodynamics-modeling-of-ibutilide-in-chinese-healthy-volunteers-and-patients-with-atrial-fibrillation-af-and-or-atrial-flutter-afl
#11
Zhijun Zeng, Li Wang, Lu Hua, Juanjuan Jiang, Huimin Pang, Yiling Huang, Yishi Li, Lei Tian
PURPOSE: The goal of this study was to develop a population pharmacokinetic (PK) and PK/pharmacodynamics (PD) model for ibutilide, to evaluate the time course of its effect on QT interval in Chinese. METHODS: The population PK and PK/PD model were developed using data from 40 Chinese healthy volunteers using nonlinear mixed-effects modeling, and the final population PK/PD model was applied on 100 patients with atrial fibrillation (AF) and/or atrial flutter (AFL)...
June 14, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28623849/population-pharmacokinetics-pharmacodynamics-of-3-4-diaminopyridine-free-base-in-patients-with-lambert-eaton-myasthenia
#12
Nilay Thakkar, Jeffrey T Guptill, Kathy Aleš, David Jacobus, Laura Jacobus, Charles Peloquin, Michael Cohen-Wolkowiez, Daniel Gonzalez
Lambert-Eaton Myasthenia (LEM) is a rare autoimmune disorder associated with debilitating muscle weakness. There are limited treatment options and 3,4-diaminopyridine free base (3,4-DAP) is an investigational orphan drug used to treat LEM-related weakness. We performed a population PK/PD analysis using 3,4-DAP and metabolite concentrations collected from a phase 2 study in LEM patients. The Triple Timed Up & Go (3TUG) assessment, which measures lower extremity weakness, was the primary outcome measure. A total of 1270 PK samples (49 patients) and 1091 3TUG data points (32 randomized patients) were included in the PK/PD analysis...
June 17, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28623508/clinical-pharmacokinetic-characteristics-of-cebranopadol-a-novel-first-in-class-analgesic
#13
Elke Kleideiter, Chiara Piana, Shaonan Wang, Robert Nemeth, Michael Gautrois
BACKGROUND AND OBJECTIVES: Cebranopadol is a novel first-in-class analgesic acting as a nociceptin/orphanin FQ peptide and opioid peptide receptor agonist with central analgesic activity. It is currently in clinical development for the treatment of chronic pain conditions. This trial focuses on the clinical pharmacokinetic (PK) properties of cebranopadol after oral single- and multiple-dose administration. METHODS: The basic PK properties of cebranopadol were assessed by means of noncompartmental methods in six phase I clinical trials in healthy subjects and patients...
June 16, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28620891/population-pharmacokinetic-modeling-of-olaratumab-an-anti-pdgfr%C3%AE-human-monoclonal-antibody-in-patients-with-advanced-and-or-metastatic-cancer
#14
Gary Mo, John R Baldwin, Debra Luffer-Atlas, Robert L Ilaria, Ilaria Conti, Michael Heathman, Damien M Cronier
BACKGROUND AND OBJECTIVES: Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population...
June 15, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28620753/population-pharmacokinetics-of-cyclosporine-a-in-japanese-renal-transplant-patients-comprehensive-analysis-in-a-single-center
#15
Akira Okada, Hidetaka Ushigome, Misaki Kanamori, Aya Morikochi, Hidefumi Kasai, Tadashi Kosaka, Takatoshi Kokuhu, Asako Nishimura, Nobuhito Shibata, Keizo Fukushima, Norio Yoshimura, Nobuyuki Sugioka
PURPOSE: Cyclosporine A (CyA), a potent immunosuppressive agent used in renal transplantation, has a narrow therapeutic window and a large variability in blood concentrations. This study aimed to develop a population pharmacokinetic (PPK) model of CyA in living-donor renal transplant patients at a single center and identify factors influencing CyA pharmacokinetics (PK). METHODS: A total of 660 points (preoperative) and 4785 points (postoperative) of blood concentration data from 98 patients who underwent renal transplantation were used...
June 15, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28619503/clinical-pharmacokinetics-of-levornidazole-in-elderly-subjects-and-dosing-regimen-evaluation-using-pharmacokinetic-pharmacodynamic-analysis
#16
Beining Guo, Gaoli He, Xiaojie Wu, Jicheng Yu, Guoying Cao, Yi Li, Yaxin Fan, Yuancheng Chen, Yaoguo Shi, Yingyuan Zhang, Jing Zhang
PURPOSE: Levornidazole, the levo-isomer of ornidazole, is a third-generation nitroimidazole derivative newly developed after metronidazole, tinidazole, and ornidazole. An open-label, parallel-controlled, single-dose study was conducted for the investigation of the pharmacokinetic (PK) profile of levornidazole and its metabolites in healthy elderly Chinese subjects, and for the evaluation of 2 dosing regimens in the elderly. METHODS: Levornidazole was intravenously administered at 500 mg to healthy elderly (aged 60-80 years) or young subjects (aged 19-45 years)...
June 12, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28616237/higher-serum-concentrations-of-vimentin-and-dakp1-are-associated-with-aggressive-breast-tumour-phenotypes-in-ghanaian-women
#17
Benjamin Arko-Boham, Justice Tanihu Lomotey, Emmanuel Nomo Tetteh, Emmanuel Ayitey Tagoe, Nii Ayite Aryee, Ewurama Ampadu Owusu, Isaac Okai, Richard Michael Blay, Joe-Nat Clegg-Lamptey
BACKGROUND: Breast cancer, the most commonly diagnosed cancer among women and leading cause of cancer-related deaths worldwide, exhibits aggressive behavior in indigenous African women evidenced by high histologic grade tumours with low hormone receptor positivity. Aggressive breast cancers grow quickly, easily metastasize and recur and often have unfavourable outcomes. The current study investigated candidate genes that may regulate tumour aggression in Ghanaian women. We hypothesize that increased expression and function of certain genes other than the widely-held view attributing breast cancer aggression in African populations to their younger population age may be responsible for the aggressive nature of tumours...
2017: Biomarker Research
https://www.readbyqxmd.com/read/28614117/role-of-amp-activated-protein-kinase-in-kidney-tubular-transport-metabolism-and-disease
#18
Roshan Rajani, Nuria M Pastor-Soler, Kenneth R Hallows
PURPOSE OF REVIEW: AMP-activated protein kinase (AMPK) is a metabolic sensor that regulates cellular energy balance, transport, growth, inflammation, and survival functions. This review explores recent work in defining the effects of AMPK on various renal tubular epithelial ion transport proteins as well as its role in kidney injury and repair in normal and disease states. RECENT FINDINGS: Recently, several groups have uncovered additional functions of AMPK in the regulation of kidney and transport proteins...
June 12, 2017: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/28612141/deterministic-identifiability-of-population-pharmacokinetic-and-pharmacokinetic-pharmacodynamic-models
#19
Vijay K Siripuram, Daniel F B Wright, Murray L Barclay, Stephen B Duffull
Identifiability is an important component of pharmacokinetic-pharmacodynamic (PKPD) model development. Structural identifiability is concerned with the uniqueness of the model parameters for a set of perfect input-output data and deterministic identifiability with the precision of parameter estimation given imperfect input-output data. We introduce two subcategories of deterministic identifiability, external and internal, and consider factors that distinguish between these forms. We define external deterministic identifiability as a function of externally controllable variables, i...
June 13, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28611092/altering-metabolic-profiles-of-drugs-by-precision-deuteration-2-discovery-of-a-deuterated-analog-of-ivacaftor-with-differentiated-pharmacokinetics-for-clinical-development
#20
Scott L Harbeson, Adam J Morgan, Julie F Liu, Ara M Aslanian, Sophia Nguyen, Gary W Bridson, Christopher L Brummel, Lijun Wu, Roger D Tung, Lana Pilja, Virginia Braman, Vinita Uttamsingh
Ivacaftor is currently used for the treatment of cystic fibrosis as both monotherapy (Kalydeco®) and combination therapy with lumacaftor (Orkambi®). Each therapy targets specific patient populations: Kalydeco treats patients carrying one of nine gating mutations in the cystic fibrosis transmembrane conductance regulator protein (CFTR), while Orkambi treats patients homozygous for the F508del CFTR mutation. In this study, we explored the pharmacological and metabolic effects of precision deuteration chemistry on ivacaftor by synthesizing two novel deuterated ivacaftor analogs, CTP-656 (d9-ivacaftor) and d18-ivacaftor...
June 13, 2017: Journal of Pharmacology and Experimental Therapeutics
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